Anemia of Chronic Disease Revisited: Hepcidin Dysregulation, Erythropoietic Failure, and Emerging Roles of SGLT2
Mohammed Abdulgayoom1, Awni Alshurafa1, Rasha Kaddoura2
1Department of Hematology, National Center for Cancer Care and Research (NCCCR), Hamad Medical Corporation, Doha, Qatar.
Insights
Sodium-glucose cotransporter 2 (SGLT2) inhibitors show promise in treating anemia of chronic disease (ACD) by addressing underlying inflammation and iron regulation. Further research is needed to confirm their role in managing this common complication.
Area of Science:
- Hematology
- Nephrology
- Endocrinology
- Immunology
Background:
- Anemia of chronic disease (ACD), or anemia of inflammation, is common in chronic infections, autoimmune diseases, malignancy, and kidney disease.
- ACD involves inflammation-driven iron sequestration, impaired erythropoietin (EPO) production, and suppressed erythropoiesis.
- Current ACD treatments like iron and erythropoiesis-stimulating agents (ESAs) have limitations due to hepcidin, EPO resistance, and safety concerns.
Purpose of the Study:
- To re-examine ACD through an integrated framework of hepcidin dysregulation, iron sequestration, and inflammatory inhibition of the EPO axis.
- To synthesize emerging evidence on sodium-glucose cotransporter 2 (SGLT2) inhibitors' effects on hemoglobin and hematocrit.
- To critically re-appraise ACD paradigms and explore pathway-level approaches versus downstream replacement strategies.
Main Methods:
- Review and synthesis of existing literature on ACD pathophysiology and current therapies.
- Analysis of data from cardiovascular and kidney disease trials investigating SGLT2 inhibitors.
- Exploration of mechanistic studies suggesting how SGLT2 inhibitors impact iron-erythropoietic pathways.
Main Results:
- SGLT2 inhibitors demonstrated sustained increases in hemoglobin/hematocrit in cardiovascular and kidney disease trials, even in non-diabetic populations.
- Mechanistic insights suggest SGLT2 inhibitors may reduce hepcidin, improve iron mobilization, augment EPO, and reduce inflammation.
- These effects are relevant to ACD pathophysiology, contrasting with current 'replacement' therapies.
Conclusions:
- SGLT2 inhibition presents a potential pathway-level approach for ACD, distinct from traditional iron and ESA therapies.
- Further biomarker-guided studies are warranted to investigate SGLT2 inhibitors as adjunctive therapy for inflammatory anemia.
- Current evidence is hypothesis-generating, emphasizing the need for more research before clinical practice changes.
Abstract:
Anemia of chronic disease (ACD), also referred to as anemia of inflammation, is a prevalent and clinically significant complication of chronic infection, autoimmune disease, malignancy, and chronic kidney disease. It is characterized by inflammation-driven iron sequestration, impaired erythropoietin (EPO) production and signaling, and suppression of effective erythropoiesis. Current therapies (iron supplementation and erythropoiesis-stimulating agents) often address downstream consequences and may be limited by hepcidin-driven functional iron deficiency, cytokine-mediated EPO resistance, and safety concerns in vulnerable populations. This review re-examines ACD through an integrated framework of hepcidin dysregulation, iron sequestration, and inflammatory inhibition of the EPO axis. We then synthesize emerging evidence that sodium-glucose cotransporter 2 (SGLT2) inhibitors produce sustained increases in hemoglobin/hematocrit beyond transient hemoconcentration across cardiovascular and kidney disease trials, including in non-diabetic populations. Mechanistic studies suggest a coordinated biologic response that may include reduced hepcidin, improved iron mobilization, physiologic augmentation of endogenous EPO, and attenuation of systemic inflammation-pathways directly relevant to ACD. We critically re-appraise current ACD paradigms by contrasting downstream "replacement" strategies (iron and ESAs) with pathway-level approaches (HIF-PHIs and SGLT2 inhibition), and we outline biomarker-guided study designs to test whether SGLT2 inhibition may act as an adjunctive physiologic modulator of iron-erythropoietic crosstalk in well-phenotyped inflammatory anemia cohorts, while emphasizing that current evidence remains hypothesis-generating rather than practice-changing.
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